Compounds have been found which exhibit anti-inflammatory, analgesic and antipyretic activity, (in addition to inhibiting hormone-induced uterine contractions and certain types of cancer growth) through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Initially, only one form of cyclooxygenase was known, this corresponding to cyclooxygenase-1 or the constitutive enzyme, as originally identified in bovine seminal vesicles. This enzyme has been cloned, sequenced and characterized from various sources including sheep, mouse and man. Prostaglandins have also been found to have both physiological and pathological roles. Cyclooxygenase-1 is responsible for endogenous basal release of prostaglandins and is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow. Non-steroidal anti-inflammatory drugs (NSAIDS) have been found to inhibit the cyclooxygenase-1 enzyme and thereby exhibit anti-inflammatory, analgesic and antipyretic properties.
While NSAIDS exhibit excellent anti-inflammatory, analgesic and antipyretic properties and possess additional benefits such as quick onset times, NSAIDS have a potential for gastrointestinal toxicity, and/or renal side effects.
More recently, the gene for a second inducible form of cyclooxygenase, referred to as cyclooxygenase-2, has been cloned, sequenced and characterized in chicken, marine and human sources. This gene, termed cyclooxygenase-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. In contrast to cyclooxygenase-1, cyclooxygenase-2 is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would normally occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines. Therefore, a selective inhibitor of cyclooxygenase-2 has similar anti-inflammatory, analgesic and antipyretic properties to those obtained by inhibition of the cyclooxygenase-1 through use of an NSAIDS.
A number of cyclooxygenase-2 inhibitors are known. For example, cyclooxygenase-2 inhibitors are disclosed in U.S. Pat. Nos. 5,393,790; 5,409,944; 5,418,254; 5,420,343; 5,436,265; 5,474,995; 5,476,944; 5,486,534; 5,510,368; 5,521,213; 5,536,752; 5,547,975; 5,550,142; 5,552,422; 5,565,482; 5,576,339; 5,580,985; 5,585,504; 5,593,994 and 5,596,008.
While cyclooxygenase-2 inhibitors possess similar anti-inflammatory, analgesic and antipyretic activity to NSAIDS, cyclooxygenase-2 inhibitors also exhibit a diminished tendency to induce some of the mechanism-based side effects that may occur with the use of NSAIDs. In particular, cyclooxygenase-2 inhibitors appear to have a reduced potential for gastrointestinal toxicity and renal side effects, a reduced effect on bleeding times and possibly a diminished ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
However, while cyclooxygenase-2 inhibitors do possess potential benefits relating to reduced side effects, they are generally slow acting relative to cyclooxygenase-1 inhibitors such as NSAIDs or acetaminophen. Therefore, a patient using them for analgesia perceives that they possess an unsatisfactorily long onset period in providing the desired analgesia.
The compositions claimed herein offer the benefits of quicker onset for analgesia relative to cyclooxygenase-2 inhibitors used alone. The claimed compositions further reduce the amount of cyclooxygenase-1 inhibitors administered and thereby reduce the potential for gastrointestinal toxicity. Such combinations further provide longer duration of action, such as “once daily dosing”, without losing the benefit of the fast onset of analgesia associated with the use of cyclooxygenase-1 inhibitors. In still a further benefit of the present invention, the combinations of the claimed compositions are found to be synergistic in that the onset time of the cyclooxygenase-1 inhibitors (and therefore the claimed composition) is reduced relative to the onset times of either component used alone. In other words, the onset of the cyclooxygenase-1 inhibitor component (e.g. NSAID) is unexpectedly potentiated by the presence of the cyclooxygenase-2 inhibitor.